OBJECTIVE: Genetic factors have been proposed as modulators of the timing of natural menopause. Single nucleotide polymorphisms (SNPs) of genes associated with thrombophilia and vascular homeostasis may interfere with ovarian function and thus are candidate genes for early menopause. We attempted to assess the association of SNPs and the timing of menarche and natural and surgical menopause in an ethnically homogenous cohort of Middle European white women. DESIGN: In the present cross-sectional study, eight SNPs of six genes involved in vascular function and homeostasis were analyzed by sequencing-on-chip using solid-phase polymerase chain reaction on oligonucleotide microarrays in 728 white women: factor V (F5) Leiden G1691A, factor II (F2) prothrombin G20210A, plasminogen activator inhibitor1 (PAI-1) 4G/5G, angiotensinogen (AGT) Met235Thr, endothelial nitric oxide synthase (NOS3) T768C and NOS3 Glu298Asp, apolipoprotein E-1 (APOE-1) Cys112Arg, and APOE-2 Arg158Cys. The women's reproductive and medical histories were correlated to genotypes. RESULTS: In a univariate analysis, current smoking (P = 0.01) and the presence of at least one mutant allele of F5 Leiden (P = 0.03) and APOE-2 (P = 0.03) were significantly associated with a reduced age at natural menopause. The presence of at least one mutant allele of F5 Leiden (P = 0.02) and a body mass index above 25 kg/m (P = 0.009) were significantly associated with an increased risk for surgical menopause by premenopausal hysterectomy (odds ratio = 2.6, 95% CI, 1.2-5.6; odds ratio = 1.9, 95% CI, 1.2-3.0, respectively). Age at menarche was not affected by the carriage of any of the investigated SNPs. Applying stepwise linear regression models considering all two-way interactions, no interactions were found among different SNPs or between SNPs and environmental and lifestyle parameters. CONCLUSION: We identified various genetic and personal history parameters influencing age at natural menopause and the risk of undergoing premenopausal hysterectomy. To the best of our knowledge, we present the largest study to date determining SNPs as contributors to the genetic control of the timing of natural and surgical menopause.
OBJECTIVE: Genetic factors have been proposed as modulators of the timing of natural menopause. Single nucleotide polymorphisms (SNPs) of genes associated with thrombophilia and vascular homeostasis may interfere with ovarian function and thus are candidate genes for early menopause. We attempted to assess the association of SNPs and the timing of menarche and natural and surgical menopause in an ethnically homogenous cohort of Middle European white women. DESIGN: In the present cross-sectional study, eight SNPs of six genes involved in vascular function and homeostasis were analyzed by sequencing-on-chip using solid-phase polymerase chain reaction on oligonucleotide microarrays in 728 white women: factor V (F5) Leiden G1691A, factor II (F2) prothrombin G20210A, plasminogen activator inhibitor1 (PAI-1) 4G/5G, angiotensinogen (AGT) Met235Thr, endothelial nitric oxide synthase (NOS3) T768C and NOS3Glu298Asp, apolipoprotein E-1 (APOE-1) Cys112Arg, and APOE-2Arg158Cys. The women's reproductive and medical histories were correlated to genotypes. RESULTS: In a univariate analysis, current smoking (P = 0.01) and the presence of at least one mutant allele of F5 Leiden (P = 0.03) and APOE-2 (P = 0.03) were significantly associated with a reduced age at natural menopause. The presence of at least one mutant allele of F5 Leiden (P = 0.02) and a body mass index above 25 kg/m (P = 0.009) were significantly associated with an increased risk for surgical menopause by premenopausal hysterectomy (odds ratio = 2.6, 95% CI, 1.2-5.6; odds ratio = 1.9, 95% CI, 1.2-3.0, respectively). Age at menarche was not affected by the carriage of any of the investigated SNPs. Applying stepwise linear regression models considering all two-way interactions, no interactions were found among different SNPs or between SNPs and environmental and lifestyle parameters. CONCLUSION: We identified various genetic and personal history parameters influencing age at natural menopause and the risk of undergoing premenopausal hysterectomy. To the best of our knowledge, we present the largest study to date determining SNPs as contributors to the genetic control of the timing of natural and surgical menopause.
Authors: Chunyan He; Peter Kraft; Daniel I Chasman; Julie E Buring; Constance Chen; Susan E Hankinson; Guillaume Paré; Stephen Chanock; Paul M Ridker; David J Hunter Journal: Hum Genet Date: 2010-08-24 Impact factor: 4.132
Authors: Christina T L Chen; Ching-Ti Liu; Gary K Chen; Jeanette S Andrews; Alice M Arnold; Jill Dreyfus; Nora Franceschini; Melissa E Garcia; Kathleen F Kerr; Guo Li; Kurt K Lohman; Solomon K Musani; Michael A Nalls; Leslie J Raffel; Jennifer Smith; Christine B Ambrosone; Elisa V Bandera; Leslie Bernstein; Angela Britton; Robert G Brzyski; Anne Cappola; Christopher S Carlson; David Couper; Sandra L Deming; Mark O Goodarzi; Gerardo Heiss; Esther M John; Xiaoning Lu; Loic Le Marchand; Kristin Marciante; Barbara Mcknight; Robert Millikan; Nora L Nock; Andrew F Olshan; Michael F Press; Dhananjay Vaiyda; Nancy F Woods; Herman A Taylor; Wei Zhao; Wei Zheng; Michele K Evans; Tamara B Harris; Brian E Henderson; Sharon L R Kardia; Charles Kooperberg; Yongmei Liu; Thomas H Mosley; Bruce Psaty; Melissa Wellons; Beverly G Windham; Alan B Zonderman; L Adrienne Cupples; Ellen W Demerath; Christopher Haiman; Joanne M Murabito; Aleksandar Rajkovic Journal: Hum Mol Genet Date: 2014-02-02 Impact factor: 6.150
Authors: Lisette Stolk; John R B Perry; Daniel I Chasman; Chunyan He; Massimo Mangino; Patrick Sulem; Maja Barbalic; Linda Broer; Enda M Byrne; Florian Ernst; Tõnu Esko; Nora Franceschini; Daniel F Gudbjartsson; Jouke-Jan Hottenga; Peter Kraft; Patrick F McArdle; Eleonora Porcu; So-Youn Shin; Albert V Smith; Sophie van Wingerden; Guangju Zhai; Wei V Zhuang; Eva Albrecht; Behrooz Z Alizadeh; Thor Aspelund; Stefania Bandinelli; Lovorka Barac Lauc; Jacques S Beckmann; Mladen Boban; Eric Boerwinkle; Frank J Broekmans; Andrea Burri; Harry Campbell; Stephen J Chanock; Constance Chen; Marilyn C Cornelis; Tanguy Corre; Andrea D Coviello; Pio d'Adamo; Gail Davies; Ulf de Faire; Eco J C de Geus; Ian J Deary; George V Z Dedoussis; Panagiotis Deloukas; Shah Ebrahim; Gudny Eiriksdottir; Valur Emilsson; Johan G Eriksson; Bart C J M Fauser; Liana Ferreli; Luigi Ferrucci; Krista Fischer; Aaron R Folsom; Melissa E Garcia; Paolo Gasparini; Christian Gieger; Nicole Glazer; Diederick E Grobbee; Per Hall; Toomas Haller; Susan E Hankinson; Merli Hass; Caroline Hayward; Andrew C Heath; Albert Hofman; Erik Ingelsson; A Cecile J W Janssens; Andrew D Johnson; David Karasik; Sharon L R Kardia; Jules Keyzer; Douglas P Kiel; Ivana Kolcic; Zoltán Kutalik; Jari Lahti; Sandra Lai; Triin Laisk; Joop S E Laven; Debbie A Lawlor; Jianjun Liu; Lorna M Lopez; Yvonne V Louwers; Patrik K E Magnusson; Mara Marongiu; Nicholas G Martin; Irena Martinovic Klaric; Corrado Masciullo; Barbara McKnight; Sarah E Medland; David Melzer; Vincent Mooser; Pau Navarro; Anne B Newman; Dale R Nyholt; N Charlotte Onland-Moret; Aarno Palotie; Guillaume Paré; Alex N Parker; Nancy L Pedersen; Petra H M Peeters; Giorgio Pistis; Andrew S Plump; Ozren Polasek; Victor J M Pop; Bruce M Psaty; Katri Räikkönen; Emil Rehnberg; Jerome I Rotter; Igor Rudan; Cinzia Sala; Andres Salumets; Angelo Scuteri; Andrew Singleton; Jennifer A Smith; Harold Snieder; Nicole Soranzo; Simon N Stacey; John M Starr; Maria G Stathopoulou; Kathleen Stirrups; Ronald P Stolk; Unnur Styrkarsdottir; Yan V Sun; Albert Tenesa; Barbara Thorand; Daniela Toniolo; Laufey Tryggvadottir; Kim Tsui; Sheila Ulivi; Rob M van Dam; Yvonne T van der Schouw; Carla H van Gils; Peter van Nierop; Jacqueline M Vink; Peter M Visscher; Marlies Voorhuis; Gérard Waeber; Henri Wallaschofski; H Erich Wichmann; Elisabeth Widen; Colette J M Wijnands-van Gent; Gonneke Willemsen; James F Wilson; Bruce H R Wolffenbuttel; Alan F Wright; Laura M Yerges-Armstrong; Tatijana Zemunik; Lina Zgaga; M Carola Zillikens; Marek Zygmunt; Alice M Arnold; Dorret I Boomsma; Julie E Buring; Laura Crisponi; Ellen W Demerath; Vilmundur Gudnason; Tamara B Harris; Frank B Hu; David J Hunter; Lenore J Launer; Andres Metspalu; Grant W Montgomery; Ben A Oostra; Paul M Ridker; Serena Sanna; David Schlessinger; Tim D Spector; Kari Stefansson; Elizabeth A Streeten; Unnur Thorsteinsdottir; Manuela Uda; André G Uitterlinden; Cornelia M van Duijn; Henry Völzke; Anna Murray; Joanne M Murabito; Jenny A Visser; Kathryn L Lunetta Journal: Nat Genet Date: 2012-01-22 Impact factor: 38.330